The human brain contains billions of axons that follow precise pathways essential for the establishment of functional connections. Despite intensive efforts, only few disorders resulting from errors in axon guidance have been identified wherein, their molecular etiologies have not been elucidated. I have identified mutations in PCDH12 in families presenting abnormalities in brain connectivity. I now plan to broaden the screening to identify additional novel gene mutations related to brain wiring defects. Identifying genetic causes will not only shed light on the pathological mechanisms but also will provide insight about the cellular and molecular machinery during development. A major challenge for understanding neurodevelopmental disorders to date, has been the lack of affected tissue. The capacity to differentiate neural tissue from patient induced pluripotent stem cells (iPSCs) opens an exciting avenue to reveal unique human features of disease. Thus, during the mentored phase of this award, I propose to utilize a combination of iPSC and animal models to uncover the molecular basis underlying axon guidance and neural circuit formation in the absence of PCDH12. During the independent phase I will conduct mechanistic studies to characterize the functional interaction between PCDH12 and Cofilin pertaining to axon guidance in both iPSC and mouse disease models, utilizing the skills obtained during the mentored phase of the award. To pursue the proposed research, I have generated iPSCs from patient and control fibroblasts and I have started the characterization of Pcdh12-/- mice. My long-term goal is to combine my background in neuronal death and synapse formation with the expertise in axon guidance; which will be acquired during the proposed training, in order to better understand brain wiring defects. I aim to integrate human genetics, animal, and stem cell disease models to elucidate the molecular mechanisms pertaining to neural circuit formation. I believe that this combination of techniques will provide insights into how the human brain develops and revolutionize our understanding of neurodevelopmental disorders, laying the groundwork for developing new therapies.